Abstract

A 70-kb virulence plasmid (sometimes called pYV) enables
Yersinia spp. to survive and multiply in the lymphoid
tissues of their host. It encodes the Yop virulon, a system consisting
of secreted proteins called Yops and their dedicated type III secretion
apparatus called Ysc. The Ysc apparatus forms a channel composed of 29
proteins. Of these, 10 have counterparts in almost every type III
system. Secretion of some Yops requires the assistance, in the
bacterial cytosol, of small individual chaperones called the Syc
proteins. These chaperones act as bodyguards or secretion pilots for
their partner Yop. Yop proteins fall into two categories. Some are
intracellular effectors, whereas the others are “translocators”
needed to deliver the effectors across the eukaryotic plasma membrane,
into eukaryotic cells. The translocators (YopB, YopD, LcrV) form a pore
of 16–23 Å in the eukaryotic cell plasma membrane. The effector Yops
are YopE, YopH, YpkA/YopO, YopP/YopJ, YopM, and YopT. YopH is a
powerful phosphotyrosine phosphatase playing an antiphagocytic role by
dephosphorylating several focal adhesion proteins. YopE and YopT
contribute to antiphagocytic effects by inactivating GTPases
controlling cytoskeleton dynamics. YopP/YopJ plays an
anti-inflammatory role by preventing the activation of the
transcription factor NF-κB. It also induces rapid apoptosis
of macrophages. Less is known about the role of the phosphoserine
kinase YopO/YpkA and YopM.

Yersinia pestis has in
the past caused social devastation on a scale unmatched by any other
infectious agent. Although it is presently not a major public health
problem, there are still at least 2,000 cases of plague reported
annually, and plague has recently been recognized as a re-emerging
disease by the World Health Organization. The pathogenicity of
Yersinia results from its impressive ability to overcome the
defenses of the mammalian host and to overwhelm it with massive growth.
Multiplication of Y. pestis is largely extracellular (1). In
infected mice, significant levels of interferon γ (IFN-γ) and tumor
necrosis factor α (TNF-α) arise only just before death. In
contrast, prompt and marked synthesis of these cytokines is observed
upon infection with avirulent strains (2). All these observations
suggest that the pathogenicity arsenal of Y. pestis protects
the bacterium from phagocytosis and slows down the onset of the
inflammatory response. The closely related food-borne pathogens
Yersinia pseudotuberculosis and Yersinia
enterocolitica cross the intestinal barrier and multiply in the
abdominal lymphoid tissues. Although they cause infections that are
generally self-limited, they share with Y. pestis the Yop
virulon, the core of the Yersinia pathogenicity arsenal.
This Yop virulon allows extracellular Yersinia docked at the
surface of a host cell to inject specialized proteins, called Yops,
across the plasma membrane. The injected Yops disturb the dynamics of
the cytoskeleton and block the production of pro-inflammatory
cytokines, thereby favoring the survival of the invading
Yersinia. The Yop virulon is thus a complex weapon for close
combat with cells of the immune system (for an exhaustive review see
ref. 3). It is the archetype of the so-called “type III
secretion” virulence mechanisms now identified in more than a dozen
major animal or plant pathogens (for review see ref. 4).

A Device to Inject Bacterial Proteins Across Eukaryotic Cell
Membranes

The Yersinia Ysc Secretion Apparatus.

“Yop secretion” was discovered around 1990 by trying to
understand the mysterious phenomenon of Ca2+
dependency: when incubated at 37°C in the absence of
Ca2+ ions, Yersinia bacteria do not
grow but, instead release large amounts of proteins called Yops into
the culture supernatant (5). Although it is generally referred to as
Yop “secretion,” it is not a physiological secretion but rather a
massive leakage resulting from the artificial opening of an otherwise
tightly controlled delivery apparatus. Despite the fact that it is
presumably artifactual, this observation turned out to be of paramount
importance because it allowed the genetic analysis that led to the
identification of 29 ysc (Yop
secretion) genes involved in the process of Yop
release.

Among the 29 Ysc proteins, 10 (YscC, -J, -N, -O, -Q, -R, -S, -T,
-U, and -V) appear to have counterparts in almost every type III
secretion apparatus. YscC belongs to the family of secretins, a group
of outer membrane proteins involved in the transport of various
macromolecules and filamentous phages across the outer membrane.
Similar to other secretins, it forms a ring-shaped structure with an
external diameter of about 200 Å and an apparent central pore of about
50 Å (6). At least one disulfide bond is essential for its assembly
(7), and its proper insertion in the outer membrane requires the
presence of an ancillary lipoprotein called YscW (6). Four proteins
(YscD, -R, -U, and -V, formerly called LcrD) have been shown, and two
other proteins (YscS and -T) have been predicted to span the inner
membrane. The secretion process absolutely requires YscN, a 47.8-kDa
protein with ATP-binding motifs (Walker boxes A and B) resembling the
β catalytic subunit of
F0F1 proton translocase and
related ATPases (8). YscJ is a lipoprotein that has not been localized
yet, but its counterpart in Pseudomonas syringae has been
shown to span the inner and outer membranes (9). Little is known about
the YscL, YscQ, and Ysc proteins, which are less conserved. Finally,
the two proteins YscO and YscP are themselves released upon
Ca2+ chelation, suggesting that they belong to
the external part of the apparatus (10, 11, 69). Fig.
1 summarizes current knowledge of the Yop
virulon.

The Yop virulon. When Yersinia are placed at 37°C in a
rich environment, the Ysc secretion channel is installed. Proteins
YscD, -R, -S, -T, -U, and -V are localized in the inner membrane (IM),
whereas YscC and YscP are exposed at the bacterial surface. Lipoprotein
YscW stabilizes YscC. YscN belongs to the family of ATPases. A stock of
Yop proteins is synthesized, and some of them are capped with their
specific Syc chaperone. As long as there is no contact with a
eukaryotic cell, a stop-valve, possibly made of YopN, TyeA, and LcrG,
blocks the Ysc secretion channel. On contact with a eukaryotic target
cell, the bacterium attaches tightly by interaction between its YadA
and Inv adhesins and β-integrins, and the secretion channel opens.
The Yops are then transported through the Ysc channel, and the Yop
effectors are translocated across the plasma membrane, guided by the
translocators YopB, YopD, and LcrV.

Assembly of the bacterial flagellum also involves a type III
secretion system. This system has no secretin but it has counterparts
to the nine other conserved Ysc proteins (YscJ, -N, -O, -Q, -R, -S, -T,
-U, and -V). All these proteins belong to the most internal part of the
basal body—i.e., the MS ring, the C ring, and the ATPase (reviewed in
ref. 12), which is in good agreement with the localization proposed for
the homologous Ysc proteins. Thus, the similarity between the Ysc
apparatus and the flagellum export apparatus resides in their most
inner part. While the Salmonella and Shigella
“injectisomes” can be visualized by electron microscopy (13, 14),
such visualization is not yet the case for the Yersinia Ysc
apparatus. Little is known about the actual mechanism of export, but it
is generally assumed that the Ysc apparatus serves as a hollow conduit
through which the exported proteins travel to cross the two membranes
and the peptidoglycan barrier, in one step. Whether proteins travel
folded or unfolded has not yet been demonstrated but, given the size of
channel, it is likely that they travel at least partially unfolded.

Translocation of Effectors Across Animal Cell Membranes.

Purified secreted Yops have no cytotoxic effect on cultured cells,
although live extracellular Yersinia have such an activity.
Cytotoxicity nevertheless depends on the capacity of the bacterium to
secrete YopE and YopD, and YopE alone is cytotoxic when microinjected
into the cells (15). This observation led to the hypothesis that YopE
is a cytotoxin that needs to be injected into the eukaryotic cell's
cytosol by a mechanism involving YopD to exert its effect (15). This
hypothesis was demonstrated by confocal laser scanning microscopy (16)
and by the adenylate cyclase reporter enzyme strategy, an approach that
is now widely used in “type III secretion” (17): infection of
eukaryotic cells with a recombinant Y. enterocolitica
producing hybrid proteins consisting of the N terminus of various Yops
(other than YopB and YopD) fused to the catalytic domain of a
calmodulin-dependant adenylate cyclase (Yop-Cya proteins)
leads to an accumulation of cyclic AMP (cAMP) in the cells. Since there
is no calmodulin in the bacterial cell and culture medium,
this accumulation of cAMP signifies the internalization of Yop-Cya into
the cytosol of eukaryotic cells (17). The phenomenon is strictly
dependant on the presence of YopD and YopB. Thus, extracellular
Yersinia inject Yops into the cytosol of eukaryotic cells by
a mechanism that involves at least YopD and YopB (18, 19). Yops are
thus a collection of intracellular “effectors” (YopE, YopH, YopM,
YpkA/YopO, YopP/YopJ, and YopT) and “translocators”
(including YopB and YopD) which are required for the translocation of
the effectors across the plasma membrane of eukaryotic cells (20).

This model of intracellular delivery of Yop effectors by
extracellular adhering bacteria is now largely supported by a number of
other results, including immunological observations. During a mouse
infection by wild-type Y. enterocolitica, the epitope formed
by amino acid residues 249–257 of the YopH effector protein is
presented by MHC class I molecules, as cytosolic proteins are, and not
by MHC class II molecules, as antigens are that are processed in
phagocytic vacuoles (21).

A Pore Formed by Translocators.

The translocators YopB and YopD have hydrophobic domains,
suggesting that they could act as transmembrane proteins (16–18, 22).
In agreement with this possibility, Yersinia has a
contact-dependent lytic activity on sheep erythrocytes, depending on
YopB and YopD (19, 23), which suggests that the translocation apparatus
involves some kind of a pore in the target cell membrane by which the
Yop effectors pass through to reach the cytosol. This YopB- and
YopD-dependent lytic activity is higher when the effector
yop genes are deleted, suggesting that the pore is normally
filled with effectors (19, 23). The idea of a translocation pore is
further supported by the observation that the membrane of
macrophage-like cells infected with an effector polymutant Y.
enterocolitica becomes permeable to small dyes (23). If the
macrophages are preloaded before the infection with a low-molecular
weight fluorescent marker, they release the fluorescent marker but not
cytosolic proteins, indicating that there is no membrane lysis but
rather insertion of a small pore (diameter 16–23 Å) into the
macrophage plasma membrane (23). The hypothesis of a channel is
reinforced by the observation that artificial liposomes that have been
incubated with Yersinia contain channels detectable by
electrophysiology (24). All these events are dependent on the presence
of the translocators YopB and YopD. These two hydrophobic Yops seem
thus to be central for the translocation of the effectors and for the
formation of a channel in lipid membranes. They presumably play
different roles in pore formation. Indeed, YopB alone can disturb
artificial membranes, whereas YopD cannot. Moreover, YopD has been
shown to end up in the cytosol of eukaryotic cells (25).

YopB and YopD are encoded by a large operon that also encodes LcrV,
LcrG, and the chaperone SycD. LcrV is a secreted Yop that has a
different name for historical reasons. The fact that LcrG and LcrV are
encoded together with translocators suggests that they could also be
involved in translocation. Not surprisingly, LcrV interacts with YopB
and YopD (26), is surface-exposed before target cell contact (27), and
is also required for translocation (26). In contrast with YopB, YopD,
and LcrV, LcrG is not a released protein, but its exact localization in
the bacterium remains elusive. It is required for efficient
translocation of Yersinia Yop effector proteins into the
eukaryotic cells but it is not required for pore formation. It binds to
heparan sulfate proteoglycans (28), but the significance of this
binding is not clear yet.

The Cytosolic Chaperones.

Type III secretion often involves a new type of small cytosolic
chaperone (29–31) (Fig. 1). In Yersinia, these chaperones
are called “Syc” (for specific Yop
chaperone) (31). Generally, they are encoded by a gene that
is located close to the gene encoding the Yop protein they serve, and
this is a useful indication to recognize them. These chaperones may not
form a single homogeneous group but rather could belong to two
different subfamilies, one devoted to effectors and one devoted to
translocators.

SycE, the chaperone of YopE, is the archetype of the first family (31).
The other representatives of this family in Yersinia are
SycH (30), SycT (32), and SycN (33, 34). They are small (14–15 kDa),
acidic (pI 4.4–5.2) proteins with a putative C-terminal amphiphilic
α-helix. They specifically bind to their cognate Yop and, in their
absence, secretion of this Yop is severely reduced, if not abolished.
Until now, research has focused mainly on SycE and SycH, but their
exact roles remain elusive. Three hypotheses have been proposed, based
on different types of observations. SycE and SycH have been shown to
bind to their partner Yop (YopE and YopH) at a unique site spanning
roughly residues 20–70 (35). Surprisingly, when this site is removed,
the cognate Yop is still secreted and the chaperone becomes dispensable
for secretion (36). This observation indicates that the binding site
itself creates the need for the chaperone and suggests that the
chaperone acts as a “bodyguard” protecting this site from
premature associations that would lead to degradation. In agreement
with this first hypothesis, SycE has been shown to protect YopE from
intrabacterial degradation: the half-life of YopE is longer in
wild-type bacteria than in sycE mutant bacteria (37, 38).
The partners in these hypothetical premature associations could be the
translocators (36), but such interactions could not be demonstrated.
Moreover, the hypothesis of premature associations with translocators
is not sufficient to explain the need for SycE. Indeed, YopE can be
secreted by the plant pathogen Xanthomonas campestris (see
below) and, although X. campestris does not synthesize
proteins resembling the Yersinia translocators, SycE is
still necessary to ensure intrabacterial stability of YopE in X.
campestris (39).

According to a second hypothesis, discussed below, SycE could act as a
secretion pilot leading the YopE protein to the secretion locus.

Finally, a recent observation suggests a third hypothesis. Both
SycE and SycH are required for efficient translocation of their partner
Yops into eukaryotic cells (35). However, when YopE is delivered by a
Yersinia polymutant strain that synthesizes an intact
secretion and translocation apparatus but no other effector than YopE,
it appears that YopE is delivered even in the absence of its chaperone
and chaperone-binding site (70). Thus, the SycE chaperone appears to be
needed only when YopE competes with other Yops for delivery. This
observation suggests that the Syc chaperones could be involved in some
kind of hierarchy for delivery. This third hypothesis about the role of
the Syc chaperones fits quite well with the observation that only a
subset of the effectors seems to have a chaperone, but it still needs
to be strengthened. Little is known about the role of SycT and SycN.
However, there is an unexpected complexity for SycN in the sense that
it requires YscB working as a cochaperone (34, 40).

SycD is the archetype of the second group of “type III
chaperones”. In its absence, translocators YopB and YopD are not
secreted and they are less detectable inside the bacterial cell (30,
41). SycD appears to be different from SycE and SycH in the sense that
it binds to several domains on YopB, reminiscent of SecB, a molecular
chaperone in Escherichia coli that is dedicated to the
export of proteins and has multiple binding sites on its targets (41).
IpgC, the related chaperone from Shigella flexneri, can
prevent the intrabacterial association between translocators IpaB and
IpaC (29). The similarity between IpgC and SycD suggested that SycD
could play a similar role and would thus prevent the intrabacterial
association of YopB and YopD. However, this turned out not to be the
case (41). Because YopB and YopD have also the capacity to bind to
LcrV, one could speculate that SycD prevents the premature association,
not between YopB and YopD but rather between YopB, YopD, and LcrV, but
this possibility has not been shown yet.

Recognition of the Transported Proteins.

Effectors delivered by type III secretion systems have no classical
cleaved N-terminal signal sequence (5). Instead, it was demonstrated in
1990 that Yops are recognized by their N terminus and that no sequence
is cleaved off during Yop secretion (5). The minimal region shown to be
sufficient for secretion was gradually reduced to 17 residues for YopH
(35), to 15 residues for YopE (35), and to 15 residues for YopN (42).

A systematic mutagenesis of the secretion signal by Anderson and
Schneewind (42, 43) led to doubts about whether this signal was encoded
in the protein. No point mutation could be identified that specifically
abolished secretion of YopE, YopN, and YopQ. Moreover, some frameshift
mutations that completely altered the peptide sequences of the YopE and
YopN signals also failed to prevent secretion. Anderson and Schneewind
(42, 43) concluded from these observations that the signal leading to
the secretion of these Yops could be in the 5′ end of the messenger RNA
rather than in the peptide sequence. Secretion would thus be
cotranslational, and translation of yop mRNA might be
inhibited either by its own RNA structure or as a result of its binding
to other regulatory elements. If this is correct, one would expect that
no Yop could be detected inside bacteria. However, while this is
reported to be true for YopQ (43), it is certainly not true for other
Yops, such as YopE. To determine whether this N-terminal (or
5′-terminal) signal is absolutely required for YopE secretion, Cheng
et al. (37) deleted codons 2–15 and they observed that 10%
of the hybrid proteins deprived of the N-terminal secretion signal were
still secreted. They inferred that there is a second secretion signal
and they showed that this second, and weaker, secretion signal
corresponds to the SycE-binding site. Not surprisingly, this secretion
signal is functional only in the presence of the SycE chaperone (37).
Whether this signal plays a role in vivo remains to be
elucidated.

Control of the Injection.

Yersinia secrete their Yops in vitro under
conditions of Ca2+ deprivation. What is the
triggering signal in vivo? Most probably contact with a
eukaryotic cell. Several reports have shown that Yop delivery by
Yersinia is a “directional” phenomenon in the sense
that most of the load is delivered inside the eukaryotic cell and that
there is little leakage (22). According to the assays used, there is
some discrepancy on the degree of “directionality” (18), but
there is no doubt that the bulk of the released Yops load ends up
inside the eukaryotic cell, indicating that contact must be the signal.
Pettersson et al. (44) provided a nice visual demonstration
of the phenomenon. By expressing luciferase under the control of a
yop promoter, they showed that active transcription of
yop genes is limited to bacteria that are in close contact
with eukaryotic cells. However, although contact is clearly the
triggering event, it is not clear yet whether a specific receptor is
involved. Pore formation in artificial membranes (24) tends to suggest
that there is none.

Effector Yops and Host Response

The Array of Yop Effectors.

Six effector Yops have been characterized: YopE, YopH, YopM,
YopJ/YopP, YopO/YpkA, and YopT (Fig.
2). Only two of them have a known enzymatic
activity: YopH is a powerful phosphotyrosine phosphatase resembling
eukaryotic phosphatases. The catalytic activity is exerted by the
C-terminal domain (≈200 residues), which contains a phosphate-binding
loop including a critical cysteine residue (Cys-403) (45).
YpkA/YopO is a serine-threonine kinase (46) which shows some
similarity with the COT (Cancer Osaka Thyroid) oncogene product, a
cytosolic serine/threonine protein kinase expressed in
hematopoietic cells and implicated in signal transduction by growth
factors. YpkA catalyzes autophosphorylation of a serine residue
in vitro. Infection of HeLa cells with a multiple
yop mutant overproducing YpkA leads to a morphological
alteration of the cells, different from those mediated by YopE and
YopH. The cells round up but do not detach from the extracellular
matrix. Inside the HeLa cells the YpkA protein is targeted to the inner
surface of the plasma membrane (47). No target protein corresponding to
YpkA/YopO has been identified yet.

Inhibition of phagocytosis by YopE, YopH, and YopT. (A)
Phagocytosis of an invading bacterium by a macrophage. The process
involves phosphorylation of focal adhesion proteins
(p130cas, Fak, Fyn, paxillin) and actin polymerization
controlled by GTPases such as RhoA and Rac. Phagocytosis is followed by
killing of the bacterium. (B) Resistance to phagocytosis
by Yersinia. On contact, Yersinia injects
Yop effectors. YopH dephosphorylates proteins from the focal adhesion
(PTPase, phosphotyrosine phosphatase); YopE inactivates Rac and cdc42
by stimulating their GTPase activity (GAP, GTPase-activating protein);
YopT deactivates RhoA.

YopM is a strongly acidic protein containing leucine-rich repeats
(LRRs) whose action and target remain unknown. It belongs to a growing
family of type III effectors that has several representatives in
Shigella (ipaH multigene family) and
Salmonella (48). YopM has been shown to traffic to the
cell's nucleus by means of a vesicle-associated pathway (49), but its
action in the nucleus remains unknown.

The Cytoskeleton Is a Target of YopE, YopH, and YopT.

Three effectors, of six identified so far, exert a negative role on
cytoskeleton dynamics and, by doing so, contribute to the strong
resistance of Yersinia to phagocytosis by macrophages (ref.
15; N. Grosdent and G.R.C., unpublished observations). Studies using
HeLa cells have shown that YopH dephosphorylates
p130cas, paxillin, and the focal adhesion kinase
(FAK) (50–52), leading to disruption of the focal adhesion and a
reduced invasin-mediated engulfment by HeLa cells (a phenomenon called
“invasion”). YopH is specifically targeted to the focal
complexes; residues 223–226, which are known to be surface-exposed,
are involved in this process. Deletion of these targeting residues
affects the anti-invasion effect. These observations also apply to
phagocytosis by the J774 macrophage–monocyte cell line, at least in
the absence of opsonization (53). In the latter cells, a catalytically
inactive YopH coprecipitates not only with
p130cas but also with FYB (54).

YopE has been known for a long time to disrupt actin filaments (15,
55), but its exact target has not yet been identified. However, YopE is
homologous to the N-terminal domain of SptP from Salmonella,
another type III effector, and it has been shown recently that this
N-terminal domain of SptP acts as a GTPase-activating protein (GAP) for
Rac-1 and Cdc42 (56). It is thus likely that YopE exerts its negative
effect on the dynamics of the cytoskeleton by exerting the same GAP
activity.

Finally, YopT exerts a dramatic depolymerizing effect on actin (32) by
modifying RhoA, a GTPase that regulates the formation of stress fibers
(57). The exact nature of the modification is not yet known.

YopP/YopJ Down-Regulates the Inflammatory Response.

As shown schematically in Fig. 3,
YopP/YopJ is a key player in the down-regulation of the
inflammatory response that is observed during Yersinia
infection. In vitro, YopP/YopJ has been shown to
counteract the normal proinflammatory response of various cell types.
Its injection reduces the release of TNF-α by macrophages (58) and of
IL-8 by epithelial (59, 60) and endothelial (G.R.C. and S.
Tötemeyer, unpublished results) cells. It also reduces the
presentation of adhesion molecules ICAM-1 and E-selectin at the surface
of endothelial cells (G.R.C. and S. Tötemeyer, unpublished
results) and hence presumably reduces the recruitment of neutrophils to
the sites of infection. All these events result from the inhibition of
the activation of NF-κB, a transcription factor known to be central
in the onset of inflammation (59, 61). The inhibition of NF-κB
activation was recently shown to result from YopP/YopJ-mediated
inhibition of IKKβ, a kinase that phosphorylates IκB, the inhibitor
of NF-κB (62). By preventing phosphorylation of IκB,
YopP/YopJ prevents its degradation and the translocation of
NF-κB to the nucleus. The inhibition of NF-κB activation is
accompanied by a lack of activation of the mitogen-activated protein
(MAP) kinases (MAPKs) c-Jun-N-terminal kinase (JNK), p38, and
extracellular signal-regulated kinase (ERK) 1 and 2 (58, 63, 64) that
is observed upon infection of macrophages by a Yersinia
producing YopP/YopJ. Lack of activation of these MAPKs results
from the inhibition of the upstream MAPK kinases (MAPKKs) by binding of
YopP/YopJ (62).

Effects of YopP/YopJ. Bacterial lipopolysaccharide (LPS), bound
to the LPS-binding protein (LBP), interacts with its receptor CD14 and
coreceptor from the Toll-like family, which leads to phosphorylation
cascades resulting in the activation of mitogen-activated protein
kinases (MAPKs) and of the kinase of the inhibitor of NF-κB (IκB).
Phosphorylation of IκB is followed by its degradation, and NF-κB
migrates to the nucleus and activates transcription of proinflammatory
cytokines, including TNF-α. Translocated YopP/YopJ prevents
the activation of the two phosphorylation cascades, and thus blocks the
release of TNF-α. YopP/YopJ also induces macrophage
apoptosis. See text for details and references.

Last but not least, YopP/YopJ also induces apoptosis in
macrophages (65, 66). This apoptosis is accompanied by cleavage
of the cytosolic protein BID, the release of cytochrome c,
and the cleavage of caspase-3 and -7 (C. Geuijen, W. Declerq, A.
Boland, P. Vandenabeele, and G.R.C., unpublished results). The release
of cytochrome c and the cleavage of BID can both be
inhibited by caspase inhibitors, suggesting that YopP/YopJ
interferes with a signaling pathway upstream of the mitochondria (C.
Geuijen, W. Declerq, A. Boland, P. Vandenabeele, and G.R.C.,
unpublished results). The reduction in the release of TNF-α is not
simply the consequence of apoptosis, because it occurs even
when apoptosis is prevented by inhibiting the activity of
caspases (61). On the contrary, apoptosis may result from the
loss of the anti-apoptotic factor NF-κB (61); however, this
hypothesis still awaits demonstration. It is thus not yet clear whether
YopP/YopJ causes apoptosis by activating a death
mechanism or by inhibiting an NF-κB-dependent survival mechanism.
Interestingly, YopP/YopJ share a high level of similarity with
AvrXv and AvrBsT from X. campestris and a protein from the
nitrogen-fixing Rhizobium.

Inhibition of Antigen-Specific T and B Lymphocytes Responses.

While they colonize and multiply in Peyer's patches or lymph nodes,
Yersinia must also encounter lymphocytes. Artificial
in vitro systems demonstrated that B and T lymphocytes are
indeed targets for Yersinia injections (ref. 67; A. P.
Boyd and G.R.C., unpublished results). Yao et al. (68)
observed that T and B cells transiently exposed to Yersinia
were impaired in their ability to be activated by means of their
antigen receptors. T cells are inhibited in their ability to produce
cytokines, and B cells are unable to up-regulate surface expression of
the costimulatory molecule B7.2, in response to antigenic stimulation.
This block of activation results from the inhibition of early
phosphorylation events (68). Through the analysis of various mutants,
YopH appeared to be the main effector involved in these events. Thus
YopH not only contributes to the evasion of the innate immune response
but it could also incapacitate the host adaptive immune response.

Footnotes

This paper was presented at the National Academy of Sciences
colloquium “Virulence and Defense in Host–Pathogen Interactions:
Common Features Between Plants and Animals,” held December 9–11,
1999, at the Arnold and Mabel Beckman Center in Irvine, CA.

A study examines trends in global fishing fleets and finds that by 2015, 68% of the global fishing fleet became motorized, and that the overall number of fleet vessels increased to 3.7 million, despite a consistent decrease in the catch per unit of effort.

A method to determine gender from fingerprints suggests pottery making was not a primarily female activity in ancient Puebloan society, challenging previous assumptions about gendered divisions of labor in ancient societies.